6286 J . Org. Chem., Vol. 65, No. 19, 2000
Notes
(R)- and (S)-cyclohexenyl phenyl glycoxilic acid. (S)-5 elutes at
approximately 17.73 min. (R)-5 elutes at approximately 13.43
min. The optical purity is >99.9% ee. 1H NMR (DMSO-D6) δ
1.50 (m, 4H), 1.85 (m, 2H), 2.00 (m, 2H), 5.70 (d, J ) 3.4 Hz,
1H), 7.23 (t, J ) 7.3 Hz, 1H), 7.31 (t, J ) 7.2 Hz, 2H), 7.46 (d, J
) 7.2 Hz, 2H). 13C NMR δ 21.84, 22.43, 24.50, 24.72, 81.44,
123.75, 123.75, 126.99, 127.48, 134.31, 139.44, 141.59, 179.76.
Mass spectrum (m/e) 232 (M+), found M+ (m/z + Na) 261.1323;
inexpensiveness, and the simplicity of the procedure. The
scope and limitation of generating tertiary alcohol centers
of medicinally valuable targets, with dioxolone deriva-
tives, are being explored.
Exp er im en ta l Section
Gen er a l. Flash chromatography was performed on EM
Science silica gel 60. Thin-layer chromatography was performed
using silica gel 60 F254 plates, and compound visualization was
effected with 10% H2SO4 containing 5% ammonium molybdate
and 0.2% ceric sulfate. All reactions were carried out in oven-
dried glassware under an argon atmosphere. KOH, (S)-(+)-
mandelic acid, pentane, trifluoromethanesulfonic acid, 10% Pd/
C, and lithium bis(trimethylsilyl)-amide were purchased from
Aldrich chemical Company. Pivaldehyde was purchased from
Lancaster chemical company.
cis-(2S,5S)-2-(ter t-Bu t yl)-5-p h e n yl-1,3-d ioxola n -4-on e
((S,S)-2). To a suspension of (S)-(+)-mandelic acid (50.0 g, 328
mmol) in pentane (500 mL) was added pivaldehyde (42.7 mL,
396 mmol), followed by addition of trifluoromethanesulfonic acid
(1.23 mL, 14 mmol) at 22 °C. To the reaction flask was added a
Dean-Stark trap. The mixture was warmed to 36 °C and allowed
to reflux for 5.5 h. The reaction mixture was allowed to cool to
room temperature, 8 wt % aqueous NaHCO3 was added. and
the reaction was concentrated in vacuo to remove volatiles
(pentane). The slurry was filtered and dried to give 68.4 g (96%)
of product with 97:3 diastereoselectivity. The formation of
dioxolone is followed by HPLC (Zorbax RX C-8, mobile phase
0.05 M NaH2PO4 (pH 2.5)/methanol (40:60, v/v)) by observing
the appearance of the dioxolone peak at approximately 8.85 min.
1H NMR (CDCl3) δ 1.11 (s, 9H), 5.27 (s, 1H), 5.35 (s, 1H), 7.46
(m, 5H). 13C NMR δ 23.82, 34.68, 109.52, 127.26, 128.94, 129.39,
133.70, 172.07. Mass spectrum (m/e) 220 (M+). Anal. Calcd for
C13H16O3: C, 70.89; H, 7.32. Found: C, 70.88; H, 7.34.
cis-(2S,5R)-2-(ter t-Bu t yl)-5-p h en yl-5-(cycloh exyl-1-ol)-
1,3-d ioxola n -4-on e ((2S,5R)-3). To a -78 °C solution of lithium
bis(trimethylsilyl)-amide (59.05 mL, 59.05 mmol, 1.0 M in
hexanes) was added crude cis-(2S,5S)-2-(tert-butyl)-5-phenyl-1,3-
dioxolan-4-one (10.0 g, 45.42 mmol, (dr 97:3), dissolved in 68
mL THF). The reaction mixture was allowed to stir for 1 h at
-78 °C, followed by the addition of neat cyclohexanone (6.59
mL, 63.59 mmol). The reaction was aged for 15 min. With
stirring, a solution of 10% NH4Cl (10.0 mL) was slowly added.
The reaction mixture was poured into a separatory funnel
containing 10% NH4Cl (131 mL). The aqueous layer was
discarded. The organic layers solvent was switched to heptane,
and the slurry was then filtered to provide 10.99 g of crude aldol
product (76%) as a white solid. The formation of (2S,5R)-3 is
followed by HPLC (Zorbax RX C-8, mobile phase 0.05 M NaH2-
PO4 (pH 2.5)/methanol (40:60, v/v)) by observing the appearance
of the (2S,5R)-3 peak at approximately 12.93 min. The minor
diastereomer (2S,5S)-3 peak is observed at 13.27 min. The
diastereomeric ratio is >99.5%. 1H NMR (CDCl3) δ 0.95 (s, 9H),
1.38-1.98 (m, 10H), 5.53 (s, 1H), 7.39 (m, 3H), 7.76 (m, 2H).
13C NMR δ 21.14, 21.23, 23.59, 25.32, 30.99, 31.22, 35.69, 86.68,
111.10, 126.98, 127.66, 128.13, 135.42, 172.54. Mass spectrum
(m/e) 301 (M+ - H2O). Anal. Calcd for C19H26O4: C, 71.67; H,
8.23. Found: C, 71.79; H, 8.15.
(S)-Cycloh ex-1-en yl-h yd r oxy-p h en yl-a cetic Acid ((S)-5).
To a 0 °C solution of cis-(2S,5R)-2-(tert-butyl)-5-phenyl-5-(cyclo-
hexyl-1-ol)-1,3-dioxolan-4-one (72.7 g, 223 mmol) in THF (727
mL) was added thionyl chloride (46.5 mL, 637 mmol), followed
by pyridine (82.8 mL, 1.02 mol). The reaction mixture was
allowed to stir for 1 h at 0 °C, followed by the addition of
saturated NH4Cl solution (543 mL). The layers were separated,
and the aqueous layer was discarded. The organic layer was
charged with 274 g of water and 128 g of KOH. The reaction
mixture was concentrated to remove volatiles, after which 136
mL of MeOH was added. The reaction mixture was then heated
to reflux for 3 h and then cooled to 22 °C. Heptane (208 g) was
charged. The layers were separated and the heptane layer was
discarded. Next, 255 mL of 6 N HCl was added, in which white
solids precipitated. The slurry was filtered to provide 51.0 g of
product (96%). The ee is determined by HPLC (Chiralpak AS,
mobile phase 95% hexane/5% IPA/0.1% TFA) by observing the
C
14H16NaO3 requires 261.1314. IR 695.7, 1056.7, 1129.8, 1723.5,
2918.9, 3408.7 cm-1
.
(S)-Cycloh exen yl P h en yl Glycoxilic Acid ((S)-1). To a
solution of (S)-cyclohex-1-enyl-hydroxy-phenyl-acetic acid (50.7
g, 218 mmol) in methanol (288 mL) was added 10% Pd/C (2.53
g). The reaction was subjected to 1 ATM of hydrogen and was
allowed to stir for 18 h. The reaction mixture was filtered
through a plug of Celite and washed with 150 mL of MeOH.
The solution solvent was switched to heptane. The solution was
distilled to a volume of 50 wt %. The slurry was filtered to
provide 47.2 g of (S)-CHPGA in 94% yield and >99.9% ee. The
ee is determined by HPLC (Chiralpak AS, mobile phase 95%
hexane/5% IPA/0.1% TFA) by observing the (R)- and (S)-1. (S)-1
elutes at approximately 9.24 min. (R)-1 elutes at approximately
6.36 min. 1H NMR (DMSO-D6) δ 1.01-1.76 (m, 10H), 2.17 (m,
1H), 5.20 (bs, 1H), 7.23 (t, J ) 7.7 Hz, 1H), 7.33 (t, J ) 7.7 Hz,
2H), 7.61 (d, J ) 7.7 Hz, 2H). 13C NMR δ 25.57, 26.27, 26.42,
27.52, 81.15, 126.10, 127.85, 128.24, 140.03, 180.97. Mass
spectrum (m/e) 234 (M+). Anal. Calcd for C14H18O3: C, 71.77;
H, 7.74. Found: C, 71.86; H, 7.77.
cis-(2S,5S)-2-(ter t-Bu tyl)-5-p h en yl-5-(cycloh exyl)-1,3-d i-
oxola n -4-on e ((S,S)-6). To a solution of cis-(2S,5S)-2-(tert-
butyl)-5-phenyl-5-(cyclohex-1-ene)-1,3-dioxolan-4-one ((S,S)-4)
(2.34 g, 7.8 mmol, dr > 99.9%) in methanol (35 mL) was added
10% Pd/C (0.23 g). The reaction was subjected to 1 atm of
hydrogen and was allowed to stir for 6 h. The reaction mixture
was filtered through a plug of Celite and concentrated in vacuo
to provide 2.21 g of crude product (95%). 1H NMR (CDCl3) δ 0.95
(s, 9H), 1.04-1.80 (m, 11H), 5.42 (s, 1H), 7.31 (m, 1H), 7.38 (tt,
J ) 1.6, 7.0 Hz, 2H), 7.67 (dt, J ) 1.6, 7.0 Hz, 2H). 13C NMR δ
23.81, 26.21, 26.36, 28.31, 35.86, 48.68, 85.45, 110.93, 125.63,
127.82, 128.12, 138.12, 173.99 Mass spectrum (m/e) 302 (M+).
Anal. Calcd for C19H26O3: C, 75.46; H, 8.67. Found: C, 75.40;
H, 8.41.
(S)-Cycloh exen yl P h en yl Glycoxilic Acid ((S)-1). To a
solution of cis-(2S,5S)-2-(tert-butyl)-5-phenyl-5-(cyclohexyl)-1,3-
dioxolan-4-one (1.0 g, 3.31 mmol) in MeOH (10 mL) was added
a 1.8 M solution of KOH (10 mL, 5 equiv). The reaction was
allowed to reflux for 3.0 h. After cooling to 22 °C, the volatiles
(MeOH) were removed in vacuo, and the aqueous reaction
mixture was extracted with ethyl acetate (50 mL). The aqueous
layer was acidified to pH 1 with 1 N HCl, and the resulting
mixture was washed with ethyl acetate (2 × 50 mL). The
combined organic layers were dried (Na2SO4), filtered, and
concentrated in vacuo to provide 0.735 g (95%, 99.9% ee) of (S)-
1. The ee is determined by HPLC (Chiralpak AS, mobile phase
95% hexane/5% IPA/0.1% TFA) by observing the (R)- and (S)-1.
(S)-1 elutes at approximately 9.24 min. (R)-1 elutes at ap-
proximately 6.36 min. 1H NMR (DMSO-D6) δ 1.01-1.76 (m,
10H), 2.17 (m, 1H), 5.20 (bs, 1H), 7.23 (t, J ) 7.7 Hz, 1H), 7.33
(t, J ) 7.7 Hz, 2H), 7.61 (d, J ) 7.7 Hz, 2H). 13C NMR δ 25.57,
26.27, 26.42, 27.52, 81.15, 126.10, 127.85, 128.24, 140.03, 180.97.
Mass spectrum (m/e) 234 (M+). Anal. Calcd for C14H18O3: C,
71.77; H, 7.74. Found: C, 71.86; H, 7.77.
cis-(2S,5R)-2-(ter t-Bu t yl)-5-p h en yl-5-(cyclop en t yl-1-ol)-
1,3-d ioxola n -4-on e ((S,R)-7). To a -78 °C solution of lithium
bis(trimethylsilyl)-amide (11.8 mL, 11.8 mmol, 1.0 M in hexanes)
in THF (13.7 mL) was added cis-(2S,5S)-2-(tert-butyl)-5-phenyl-
1,3-dioxolan-4-one (2.0 g, 9.08 mmol, dissolved in 13.7 mL of
THF). The reaction mixture was allowed to stir for 30 min at
-78 °C, followed by the addition of neat cyclopentanone (1.12
mL, 12.7 mmol). After stirring for 2 h at -78 °C, saturated
NaHPO4 solution (2.0 mL) was added. The reaction mixture was
poured into a separatory funnel containing saturated NH4Cl
solution (20 mL). The aqueous layer was separated and extracted
with ethyl acetate (2 × 300 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated in vacuo to
provide 2.4 g of crude aldol product (dr 98:2). The crude aldol
product was recrystallized from heptane to provide 2.01 g (74%)